The U54 Cooperative Contraceptive Development Research Center Grant described in this proposal is comprised of four research and development projects and one Core facility. The goals are to identify new leads that can be developed into safe and effective contraceptive methods: (I) A new progesterone receptor modulator CDB-2914, with potent anti-ovulatory effect, will be investigated in four aims: a) The molecular mechanism of action and the gene pathways involved at the ovarian level will be explored; b) CDB-2914 will be tested and formulated into vaginal gel and rings for contraceptive use in women; c) A radioimmunoassay will be established and validated for measuring serum levels of CDB-2914 for pharmacokinetic studies in women; d) The effects of CDB-2914 on human breast cells will be evaluated. Parallel studies investigating the effects of CDB-2914 on the primate endometrium and on ovarian function in women, for which funding will be requested from other sources, are also described in this document. (II) A vaginal gel containing both the microbicide Carraguard and the contraceptive steroid levonorgestrel (CARRA/LNG) will be tested for dual-protection against sexually transmitted infections and conception. Two mechanisms will be targeted for contraception in women having regular sex who will use this progestin microbicide daily: ovulation inhibition and thickening of the cervical mucus, which inhibits sperm penetration. Given the proven efficacy of LNG in emergency contraception, another goal is to test the product for use "on demand" before intercourse in women having occasional sex. (III) New compounds have been identified that are able to induce reversible germ cell depletion from the testis. The prime target of these compounds is the adherence junction (AJ) between Sertoli and germ cells in the testis. This project will focus on disruption in the AJs to induce germ cell loss without affecting hormonal pituitary-gonadal function. (IV) In a final project, sperm-supplied protein will be isolated from mammalian testes by recombinant DNA technology and will be investigated for its functional role in the development of early embryos from fertilized eggs. Antisense manipulation will be used to suppress the production of this novel sperm protein as a new method of fertility control. The Cell Culture Core facility will ensure the highest quality control standards, as well as priority access and services for Projects I, III, and IV. The Cell Culture Core Director will advise Core users concerning the latest technologies for facilitating their culture-based protocols.